The human immunodeficiency virus ("HIV") is the causative agent for acquired immunodeficiency syndrome ("AIDS")--a disease characterized by the destruction of the immune system, particularly of CD4.sup.+ T-cells, with attendant susceptibility to opportunistic infections--and its precursor AIDS-related complex ("ARC")--a syndrome characterized by symptoms such as persistent generalized lymphadenopathy, fever and weight loss.
As in the case of several other retroviruses, HIV encodes the production of a protease which carries out post-translational cleavage of precursor polypeptides in a process necessary for the formation of infectious virions (S. Crawford et al., "A Deletion Mutation in the 5' Part of the pol Gene of Moloney Murine Leukemia Virus Blocks Proteolytic Processing of the gag and pol Polyproteins", J. Virol., 53, p. 899 (1985)). These gene products include pol, which encodes the virion RNA-dependent DNA polymerase (reverse transcriptase), an endonuclease, HIV protease, (reverse transcriptase), an endonuclease, HIV protease, and ga, which encodes the core-proteins of the virion (H. Toh et al., "Close Structural Resemblance Between Putative Polymerase of a Drosophila Transposable Genetic Element 17.6 and pol gene product of Moloney Murine Leukemia Virus", EMBO J., 4, p. 1267 (1985); L. H. Pearl et al., "A Structural Model for the Retroviral Proteases", Nature, pp. 329-351 (1987); M. D. Power et al., "Nucleotide Sequence of SRV-1, a Type D Simian Acquired Immune Deficiency Syndrome Retrovirus", Science, 231, p. 1567 (1986)).
A number of synthetic anti-viral agents have been designed to target various stages in the replication cycle of HIV. These agents include compounds which block viral binding to CD4.sup.+ T-lymphocytes (for example, soluble CD4), and compounds which interfere with viral replication by inhibiting viral reverse transcriptase (for example, didanosine and zidovudine (AZT)) and inhibit integration of vital DNA into cellular DNA (M. S. Hirsh and R. T. D'Aqulia, "Therapy for Human Immunodeficiency Virus Infection", N. Eng. J. Med., 328, p. 1686 (1993)). However, such agents, which are directed primarily to early stages of viral replication, do not prevent the production of infectious virions in chronically infected cells. Furthermore, administration of some of these agents in effective amounts has led to cell-toxicity and unwanted side effects, such as anemia and bone marrow suppression.
More recently, the focus of anti-viral drug design has been to create compounds which inhibit the formation of infectious virions by interfering with the processing of viral polyprotein precursors. Processing of these precursor proteins requires the action of virus-encoded proteases which are essential for replication (Kohl, N. E. et al. "Active HIV Protease is Required for Viral Infectivity" Proc. Natl. Acad. Sci. USA, 85, p. 4686 (1988)). The anti-viral potential of HIV protease inhibition has been demonstrated using peptidal inhibitors. Such peptidal compounds, however, are typically large and complex molecules that tend to exhibit poor bioavailability and are not generally consistent with oral administration. Accordingly, the need still exists for compounds that can effectively inhibit the action of viral proteases, for use as agents for preventing and treating chronic and acute vital infections.
AIDS and other HIV related diseases often have CNS components. One such component is AIDS related dementia.
While there are a growing number of treatments for HIV and its related diseases, e.g., AIDS and ARC, such treatments have had little or no effect on the CNS effects of HIV infection.
The reason that these treatments are not as effective against the CNS effects of HIV is that the pharmaceutical compositions that characterize them are not able to cross the blood brain barrier in an amount sufficient to the effect and slow HIV infection in the CNS.
AZT, the most well-known of the HIV treatments, for example, has a brain/blood distribution of only about 0.3. And after 60 minutes, no AZT is found in brain tissue. The other HIV nucleosides, ddC, DDI and d4T, have even worse distribution profiles in the CNS.
HIV protease inhibitors also do not penetrate to the CNS at useful levels. Abbott's ABT 538, for example, displays very limited CNS penetration. Searle's inhibitor has a brain/blood distribution of 0.2 to 0.3. Merck's L-535524 has about the same distribution.
Thus, the present HIV nucleoside and protease based therapies have less than desired effects on the CNS components of HIV.